(a) Field of the Invention
The present invention relates to a water-soluble prodrug compound comprising a moiety of paclitaxel or derivatives thereof, a method of preparing the same, and a pharmaceutical composition comprising the same. More particularly, the present invention relates to a water-soluble prodrug compound comprising a moiety of paclitaxel or derivatives thereof, exhibiting good bioavailability and reduced side effect by dissolving aids, and a method of preparing the same and a pharmaceutical composition comprising the same.
(b) Related Arts
Paclitaxel (known as taxol) is a compound originally isolated from the bark of the Pacific Yew tree, and a derivative thereof (e.g. docetaxel) is semi-synthetically produced from baccatin III derivatives from the bark of the Pacific Yew tree. These paclitaxel or derivatives thereof has a diterpene structure of formula 
wherein,
if R1 is C6H6, R2 is CH3CO, this compound is paclitaxel,
if R1 is (CH3)3CO, R2 is H, this compound is docetaxel.
The research on the reaction mechanism of paclitaxel isolated by Wall and Wani in 1967 has been widely investigated has found paclitaxel to have strong toxic to cell and anticancer ability, and paclitaxel has been used as an anticancer agent manufactured by Bristol-Myers Squibb Company USA in 1992.
As paclitaxel prohibits mitotic cancer cell division rather than the conventional anticancer agent, it has relatively low toxic to body and strong anticancer ability and it was widely used in the 1990""s. This paclitaxel has been approved by the U.S. Food and Drug Administration (FDA) to treat ovarian cancer in 1992, breast cancer in 1994 and Kaposi""s sarcoma. Furthermore, paclitaxel is used for treating liver cancer, lung cancer, articula rheumacute, Alzheimer""s disease, and a clinical testing of paclitaxel with various drugs have been conducted which is expected to increase the use of paclitaxel.
Paclitaxel is insoluble in water, and it is administrated with surfactants such as Cremophor-El (polyoxyethylated castor oil), or polysorbate. For example, taxol parenteral fluid (Taxol, Birtsol-Myers Squibb) clinically applied used 6 mg of paclitaxel and 527 mg Cremophor-El as a surfactant in 1 ml of 49.7% (v/v) alcohol solution, taxotere parenteral fluid (Rhone-Poulenc Rorer) using docetaxel, paclitaxel derivatives includes 20 mg of docetaxel and 0.5 ml of polysorbate 80 as a surfactant in 1.83 mml of 13% (w/w) alcohol solution.
It was known that the Cremophore-EL or polysorbate as a surfactant causes serious side effect such as hypersensitivity reaction to some patients (Lorence, W., et al, Agents and actions, 12, 64-80, 1982). In addition, the use of vegetable oils such as Cremophore-EL causes side effect such as hypersensitive reactions. Furthermore, it is undesirable that materials with high viscosity such as alcohol and Cremophore-EL (it is changed from solution to solid according to ambient temperature) is used in parenteral fluids. The use of organic solvents such as alcohol causes problems such as hemolytic occurrence at injection area and local stimulation.
Due to these reasons, paclitaxel (taxol) produces side effects such as neuropathy, myopathy, myalgia, neutropenis and docetaxel (taxotere) produces unfavorable side effects such as stomatitis, edema and malaise.
Several methods on the development of a water-soluble prodrug compound including paclitaxel have been suggested to reduce such side effects and to improve bioavailbility. Especially, the scientists are concerned about the development of a prodrug compound using polyethyleneglycol (PEG) and actively studied. Recently, Greenwald (Enzon, Inc.) et al synthesized various paclitaxel prodrug with polyethyleneglycol (U.S. Pat. Nos. 5,614,549, 5,880,131 and 5,965,566), and water-soluble prodrug with polyethyleneglycol (U.S. Pat. No. 5,648,506). Chun Li (PG-TXL Company) et al synthesized water-soluble prodrug by reacting paclitaxel with succinic anhydride to prepare 2xe2x80x2-succinyl-paclitaxel and by reacting methyoxypolyoxyethylene amine with 2xe2x80x2-succinyl-paclitaxel (U.S. Pat. No. 5,977,163). However, it is difficult to produce formulations using these conventional compounds. Paclitaxel prodrug should be rapidly hydrolyzed by an esterase in vivo to generate physiologically active paclitaxel. However, it is known that the conventional paclitaxel prodrug has a long half life time (Txc2xd) in which paclitaxel prodrug is hydrolyzed to generate to paclitaxel, of 1 to 8 hours in rat plasma, the half-life time should be reduced about 10 minutes or less.
The object of the present invention is to provide a water-soluble prodrug compound including a moiety of paclitaxel or derivatives thereof, which is rapidly hydrolyzed in vivo so that it exhibits improved bioavailability.
Another object of the present invention is to provide a water-soluble prodrug compound including a moiety of paclitaxel or derivatives thereof, which has substantially no side effect caused by dissolving aids.
Still another object of the present invention is to provide a water-soluble prodrug compound which has a short half life time so that it""s formulation is easy.
Still another object of the present invention is to provide a method of preparing the water-soluble prodrug compound.
Still another object of the present invention is to provide a pharmaceutical composition including the water-soluble prodrug compound.
These and other objects may be achieved by a water-soluble prodrug compound including a moiety of paclitaxel or derivatives thereof, represented by formula 1. 
(wherein,
R is formulas a or b,
 less than Formula a greater than 
OCH3 
D represents a moiety of paclitaxel or derivatives thereof,
M is an integer of 1 to 6, n is an integer of 10 to 1,000,
X represents O, S or NH, and
Rxe2x80x2 represents H or CH3)
The present invention further provides a method of preparing the water-soluble prodrug compound including a moiety of paclitaxel or derivatives thereof, represented by formula 1 in which a compound of formula 2 reacts with a polyethylene glycol derivatives compound. 
(wherein,
R is formulas a or b,
OCH3xe2x80x83xe2x80x83 less than Formula a greater than 

D represents a moiety of paclitaxel or derivatives thereof,
m is an integer 1 to 6, n is an integer of 10 to 1,000,
X represents O, S or NH,
Rxe2x80x2 represents H or CH3, and
Y is a suitable leaving group such as halogen.)
The compound of formula 2 is prepared by esterifying paclitaxel or derivatives thereof and a compound of formula 4, or prepared by reacting paclitaxel or derivatives thereof with a silyl agent to prepare a compound of formula 5, reacting the compound of formula 5 with a compound of formula 4 to prepare a compound of formula 6, and deprotecting the compound of formula 6 with a weak acid. 
(wherein,
R1 is C6H6 or (CH3)3CO,
R2 is CH3CO or H,
Pt is a silyl protecting group,
Dxe2x80x2 is a moiety of the compound of formula 5,
Rxe2x80x2 is H or CH3, and
Y is a suitable leaving group such as halogen.)
The present invention provides a pharmaceutical composition including a water-soluble prodrug compound with a moiety of paclitaxel or derivatives thereof, of formula 1 as an active ingredient.